This entire project is based on the hypothesis that we can design and develop new synthetic triterpenoids that would eventually be clinically useful for chemoprevention and treatment of cancer. The project is articulated in 3 Specific Aims that cover the entire range of preclinical studies, all the way from design of new drugs; to elucidation of their biological activity, their molecular mechanisms of action, and their molecular targets; and finally, testing of efficacy for prevention of cancer in animal models of carcinogenesis that are considered relevant to actual human disease. Our Specific Aims are as follows: (1) To continue to synthesize new triterpenoids and tricyclic bis-enones (TBEs) for chemoprevention of cancer. (2) To continue to test new triterpenoids from Specific Aim 1 for biological activity in a series of cell culture assays relevant to chemoprevention and chemotherapy of cancer. Such assays measure anti-proliferative activity, induction of differentiation in tumor cells, induction of apoptosis, and anti-inflammatory activity. We will also use biotinylated triterpenoids to identify proximate molecular targets mediating the anti-proliferative, differentiating, apoptotic, and anti-inflammatory actions of triterpenoids. In conjunction with these studies, we will conduct further investigations of downstream targets and pathways, to define molecular mechanisms of action. Furthermore, new studies on effects of TBEs in gene array experiments will be started. (3) To continue to test promising new triterpenoids or TBEs in appropriate animal models for chemoprevention of cancer, with special emphasis on prevention of pancreatic, lung, and hepatocellular cancer. Particular emphasis will also be placed on testing of new triterpenoids in combination with other chemopreventive agents that are known to be effective in the animal models. In addition to the chemoprevention studies, we will do pancreatic and lung cancer experiments in a chemotherapy mode, by waiting until the animals have developed detectable cancers and then determining if our agents are effective as treatments. Triterpenoids previously synthesized with support from this grant are already in active use in Phase I clinical trials for treatment of leukemia, lymphoma, and solid tumors. Historically, many chemopreventive agents have entered clinical use for cancer prevention by first being shown to be active in treatment protocols, and we intend to continue to pursue this cross-talk between therapeutic and preventive approaches to the cancer problem with the results of the proposed new studies. PUBLIC HEALTH RELEVANCE: Relevance Lung cancer, pancreatic cancer, and liver cancer are three devastating and common forms of malignancy for which current therapies are extremely inadequate. A totally different approach to control of these three diseases would be to find some safe and effective way to prevent their occurrence. This grant application deals with the development and testing of new drugs to prevent lung, pancreatic, and liver cancer, with the eventual goal of using such drugs to prevent disease in men and women at high risk.